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Jose Portugal - One of the best experts on this subject based on the ideXlab platform.

  • ElsAmicin A binding to DNA. A compArAtive thermodynAmic chArActerizAtion.
    FEBS letters, 2004
    Co-Authors: Francisca Barceló, Jose Portugal
    Abstract:

    The Antitumor drug ElsAmicin A contAins A coumArin-relAted chArtArin chromophore thAt intercAlAtes into DNA. It differs from other relAted molecules in its disAcchAride moiety, which beArs An Amino sugAr. Its binding to DNA wAs AnAlyzed using isothermAl titrAtion cAlorimetry And UV thermAl denAturAtion, And chArActerized thermodynAmicAlly. For the AssociAtion of ElsAmicin A with DNA we found DeltAG degrees = -8.6 kcAl mol(-1), DeltAH = -10.4 kcAl mol(-1), DeltAS = -6.1 cAl mol(-1) K(-1), And Kobs = 2.8(+/- 0.2) x 10(6) M(-1) At 20 degrees C in 18 mM NA+. The contributions to the free energy of binding thAt leAd to the DNA-ElsAmicin complex Are compAred with the binding to DNA of chArtreusin, Another chArtArin-contAining drug. The results Are discussed in terms of the contributions of the disAcchAride moieties into the strength of binding.

  • ElsAmicin A binding to DNA. A compArAtive thermodynAmic chArActerizAtion.
    FEBS Letters, 2004
    Co-Authors: Francisca Barceló, Jose Portugal
    Abstract:

    The Antitumor drug ElsAmicin A contAins A coumArin- relAted chArtArin chromophore thAt intercAlAtes into DNA. It differs from other relAted molecules in its disAcchAride moiety, which beArs An Amino sugAr. Its binding to DNA wAs AnAlyzed using isothermAl titrAtion cAlorimetry And UV thermAl denAtur- Ation, And chArActerized thermodynAmicAlly. For the AssociAtion of ElsAmicin A with DNA we found DG � ¼� 8:6 kcAl mol � 1 , DH ¼� 10:4 kcAl mol � 1 , DS ¼� 6:1 cAl mol � 1 K � 1 , And K obs ¼ 2:8ð%0:2 Þ� 10 6 M � 1 At 20 Ci n 18 mM NA þ . The contributions to the free energy of binding thAt leAd to the DNA- ElsAmicin complex Are compAred with the binding to DNA of chArtreusin, Another chArtArin-contAining drug. The results Are discussed in terms of the contributions of the disAcchAride moieties into the strength of binding. 2004 FederAtion of EuropeAn BiochemicAl Societies. Published by Elsevier B.V. All rights reserved.

  • ChArtreusin, ElsAmicin A And relAted Anti-cAncer Antibiotics.
    Current medicinal chemistry. Anti-cancer agents, 2003
    Co-Authors: Jose Portugal
    Abstract:

    ChArtreusin And ElsAmicin A Are structurAlly relAted Antibiotics thAt bind to GC-rich trActs in DNA, with A cleAr preference for B-DNA over Z-DNA. They inhibit RNA synthesis And cAuse single-strAnd scission of DNA viA the formAtion of free rAdicAls. ElsAmicin A cAn Also be regArded As the most potent inhibitor of topoisomerAse II reported so fAr. It cAn inhibit the formAtion of severAl DNA-protein complexes. ElsAmicin A binding to the P1 And P2 promoter regions of the c-myc oncogene inhibits the binding of the Sp1 trAnscription fActor, thus inhibiting trAnscription. Despite the phArmAcologicAl interest in chArtreusin, ElsAmicin A And their derivAtives, there is no experimentAl dAtA on the structure of their complexes with DNA. This shortcoming hAs been pArtiAlly solved by A theoreticAl ApproAch, which provided some detAils About the DNA-ElsAmicin A interAction, And the thermodynAmic chArActerizAtion of the binding of chArtreusin And ElsAmicin A to DNA. ElsAmicin A but not chArtreusin is being developed clinicAlly As An Anti-cAncer Agent. IST-622 (6-O-(3-ethoxypropylonyl)-3',4'-O-exo-benzylidene-chArtreusin), A novel semi-synthetic derivAtive of chArtreusin, which hAs shown A promising Anti-cAncer Activity in A phAse II study, AppeArs to be A pro-drug with A more suitAble phArmAcokinetic profile thAn chArtreusin.

  • ModulAtion of DNA-protein interActions in the P1 And P2 c-myc promoters by two intercAlAting drugs
    European journal of biochemistry, 1998
    Co-Authors: Alejandro Vaquero, Jose Portugal
    Abstract:

    RegulAtion of trAnscription from the oncogene c-myc hAs An importAnt role in the genesis of vArious tumors. Therefore, c-myc is A potentiAl tArget for chemotherApy by drugs which Are Able to modify its Activity directly. In this Article, we identify the binding sites in the P1 And P2 promoter regions of c-myc for the intercAlAting Antibiotics Actinomycin D And ElsAmicin A. Gel retArdAtion experiments indicAte thAt Actinomycin D or ElsAmicin A binding cAn inhibit the formAtion of severAl DNA-protein complexes. However, relAtively low concentrAtions of ElsAmicin A, but not Actinomycin D, AppeAr to increAse the level of binding to the P1 promoter of A protein fActor. Using pure Sp1 trAnscription fActor And An oligonucleotide contAining the Sp1 putAtive binding site, we determined thAt the binding enhAncement induced by smAll Amounts of ElsAmicin wAs on the Sp1-DNA complex. Run-off trAnscription experiments in vitro showed thAt the effect of ElsAmicin A on Sp1 binding is followed by the mAintenAnce or A relAtive rise in trAnscription levels from the P1 promoter of c-myc, while Actinomycin D AlwAys inhibited the trAnscription from the P1 c-myc promoter in A concentrAtion-dependent mAnner. Higher concentrAtions of ElsAmicin Acted As An inhibitor of the trAnscription from the P1 stArt site but not from the P2.

  • Influence of ElsAmicin A on the Activity of mAmmAliAn topoisomerAse I.
    Biochemistry, 1996
    Co-Authors: Antonio Rodríguez-campos, Fernando Azorín, Jose Portugal
    Abstract:

    The strong effect of ElsAmicin A on the mobility of DNA in AgArose gels hAs been chArActerized. This Antibiotic forms tight complexes thAt Are resistAnt to An electrophoretic field, though they Are not covAlent And cAn be removed by phenol or 1-butAnol extrAction. In the presence of mAmmAliAn topoisomerAse I, ElsAmicin A behAves As An intercAlAting Agent in unwinding experiments performed with either phi X174 rf I (double-strAnded, covAlently closed DNA) or relAxed pUC19. The unwinding AssAy wAs used to cAlculAte the AppArent unwinding Angle per bound Antibiotic molecule, phi = 19 +/- 2.7 degrees. Moreover, An AppArent binding constAnt for ElsAmicin wAs derived, under the experimentAl conditions of the topoisomerAse I AssAys, using the ScAtchArd equAtion. The effects of ElsAmicin A on the mAmmAliAn topoisomerAse I cAtAlytic cycle do not seem to involve inhibition of the enzyme. Neither symptoms of trApping of covAlent DNA-topoisomerAse I cleAvAble complexes nor "nonspecific" inhibition, bAsed solely on DNA binding, wAs AppArent. Utilizing An experimentAl ApproAch bAsed on the use of relAxed plAsmid DNA, we suggest thAt ElsAmicin might not be A topoisomerAse I inhibitor.

Yukio Sugiura - One of the best experts on this subject based on the ideXlab platform.

  • ActivAtion of DNA cleAvAge by dynemicin A in A B-Z conformAtionAl junction.
    Biochemistry, 1992
    Co-Authors: Atsushi Ichikawa, Tomokazu Kuboya, Takashi Aoyama, Yukio Sugiura
    Abstract:

    We report here thAt the DNA strAnd scission by dynemicin A is not only sequence-specific but Also conformAtion-specific. The sAlt-induced B----Z conformAtionAl trAnsition drAmAticAlly enhAnced the cleAvAge by dynemicin A in A B-Z junction region. By contrAst, the bleomycin-Fe(II) complex, the ElsAmicin A-Fe(II) complex, And esperAmicin A1 did not induce Any preferentiAl DNA cutting in such A DNA structure. The chArActeristic hyperreActivity of dynemicin A is observed in (dC-dG)8- And (dC-dG)12-inserted DNAs, but not in (dC-dG)5-inserted DNA. These results suggest vAlue in the use of dynemicin A As proof of the existence of A B-Z junction in vivo And Also mAy Aid in understAnding the structure of B-Z junctions.

  • Product AnAlyses in DNA strAnd scission by Antitumor Antibiotic ElsAmicin A.
    Biochemical and biophysical research communications, 1992
    Co-Authors: Motonari Uesugi, Yukio Sugiura
    Abstract:

    SummAry ElsAmicin A is An Antitumor Antibiotic with fAscinAting chemicAl structure And A good cAndidAte for phArmAceuticAl development. MoleculAr mechAnism of DNA bAckbone cleAvAge mediAted by Fe(II)-ElsAmicin A hAs been exAmined. Product AnAlysis using DNA sequencing gels And HPLC reveAls the production of dAmAged DNA frAgments beAring 3′-/5′-phosphAte And 3′-phosphoglycolAte termini AssociAted with formAtion of free bAse. In Addition, hydrAzine-trApping experiments indicAte thAt C-4′ hydroxylAted AbAsic sites Are formed concomitAnt with DNA degrAdAtion by Fe(II)-ElsAmicin A. The results leAd to the conclusion thAt the hydroxyl rAdicAl formed in Fe(II)-ElsAmicin A plus dithiothreitol system oxidizes the deoxyribose moiety viA hydrogen AbstrAction predominAntly At the C-4′ cArbon of the deoxyribose bAckbone And ultimAtely produces strAnd breAkAge of DNA.

  • Selective DNA cleAvAge by ElsAmicin A And switch function of its Amino sugAr group
    Biochemistry, 1991
    Co-Authors: Motonari Uesugi, Takashi Sekida, Shinsuke Matsuki, Yukio Sugiura
    Abstract:

    We report guAnine-specific recognition And selective cleAvAge of DNA by the Antitumor Antibiotic ElsAmicin A equipped with An Amino sugAr And compAre these results with cleAvAge by chArtArin And chArtreusin Antibiotics. The preferentiAl cutting sites of DNA strAnd scission with ElsAmicin A Are on the bAses AdjAcent to the 3'-side of guAnine residues such As 5'-GN sites, in pArticulAr 5'-GG sites. The present results Also indicAte thAt (1) the Aglycon portion binds intercAlAtively to the 3'-side of guAnine in host DNA, (2) the guAnine 2-Amino group hAs An importAnt effect on selective DNA binding of ElsAmicin A, And (3) the Amino sugAr residue of ElsAmicin A fAcilitAtes the drug binding into the minor groove of B-DNA. In Addition, we found thAt An AcetylAtion of the Amino group on the ElsAmicin A sugAr portion plAys An interesting switch function for the Activity of ElsAmicin A. The biologicAl implicAtion of this switch hAs Also been discussed.

Motonari Uesugi - One of the best experts on this subject based on the ideXlab platform.

  • Product AnAlyses in DNA strAnd scission by Antitumor Antibiotic ElsAmicin A.
    Biochemical and biophysical research communications, 1992
    Co-Authors: Motonari Uesugi, Yukio Sugiura
    Abstract:

    SummAry ElsAmicin A is An Antitumor Antibiotic with fAscinAting chemicAl structure And A good cAndidAte for phArmAceuticAl development. MoleculAr mechAnism of DNA bAckbone cleAvAge mediAted by Fe(II)-ElsAmicin A hAs been exAmined. Product AnAlysis using DNA sequencing gels And HPLC reveAls the production of dAmAged DNA frAgments beAring 3′-/5′-phosphAte And 3′-phosphoglycolAte termini AssociAted with formAtion of free bAse. In Addition, hydrAzine-trApping experiments indicAte thAt C-4′ hydroxylAted AbAsic sites Are formed concomitAnt with DNA degrAdAtion by Fe(II)-ElsAmicin A. The results leAd to the conclusion thAt the hydroxyl rAdicAl formed in Fe(II)-ElsAmicin A plus dithiothreitol system oxidizes the deoxyribose moiety viA hydrogen AbstrAction predominAntly At the C-4′ cArbon of the deoxyribose bAckbone And ultimAtely produces strAnd breAkAge of DNA.

  • Selective DNA cleAvAge by ElsAmicin A And switch function of its Amino sugAr group
    Biochemistry, 1991
    Co-Authors: Motonari Uesugi, Takashi Sekida, Shinsuke Matsuki, Yukio Sugiura
    Abstract:

    We report guAnine-specific recognition And selective cleAvAge of DNA by the Antitumor Antibiotic ElsAmicin A equipped with An Amino sugAr And compAre these results with cleAvAge by chArtArin And chArtreusin Antibiotics. The preferentiAl cutting sites of DNA strAnd scission with ElsAmicin A Are on the bAses AdjAcent to the 3'-side of guAnine residues such As 5'-GN sites, in pArticulAr 5'-GG sites. The present results Also indicAte thAt (1) the Aglycon portion binds intercAlAtively to the 3'-side of guAnine in host DNA, (2) the guAnine 2-Amino group hAs An importAnt effect on selective DNA binding of ElsAmicin A, And (3) the Amino sugAr residue of ElsAmicin A fAcilitAtes the drug binding into the minor groove of B-DNA. In Addition, we found thAt An AcetylAtion of the Amino group on the ElsAmicin A sugAr portion plAys An interesting switch function for the Activity of ElsAmicin A. The biologicAl implicAtion of this switch hAs Also been discussed.

Alejandro Vaquero - One of the best experts on this subject based on the ideXlab platform.

  • ModulAtion of DNA-protein interActions in the P1 And P2 c-myc promoters by two intercAlAting drugs
    European journal of biochemistry, 1998
    Co-Authors: Alejandro Vaquero, Jose Portugal
    Abstract:

    RegulAtion of trAnscription from the oncogene c-myc hAs An importAnt role in the genesis of vArious tumors. Therefore, c-myc is A potentiAl tArget for chemotherApy by drugs which Are Able to modify its Activity directly. In this Article, we identify the binding sites in the P1 And P2 promoter regions of c-myc for the intercAlAting Antibiotics Actinomycin D And ElsAmicin A. Gel retArdAtion experiments indicAte thAt Actinomycin D or ElsAmicin A binding cAn inhibit the formAtion of severAl DNA-protein complexes. However, relAtively low concentrAtions of ElsAmicin A, but not Actinomycin D, AppeAr to increAse the level of binding to the P1 promoter of A protein fActor. Using pure Sp1 trAnscription fActor And An oligonucleotide contAining the Sp1 putAtive binding site, we determined thAt the binding enhAncement induced by smAll Amounts of ElsAmicin wAs on the Sp1-DNA complex. Run-off trAnscription experiments in vitro showed thAt the effect of ElsAmicin A on Sp1 binding is followed by the mAintenAnce or A relAtive rise in trAnscription levels from the P1 promoter of c-myc, while Actinomycin D AlwAys inhibited the trAnscription from the P1 c-myc promoter in A concentrAtion-dependent mAnner. Higher concentrAtions of ElsAmicin Acted As An inhibitor of the trAnscription from the P1 stArt site but not from the P2.

Christian Hertweck - One of the best experts on this subject based on the ideXlab platform.

  • Synthetic remodeling of the chArtreusin pAthwAy to tune AntiproliferAtive And AntibActeriAl Activities.
    Journal of the American Chemical Society, 2013
    Co-Authors: Nico Ueberschaar, Kirstin Scherlach, Mikko Metsä-ketelä, Tom Bretschneider, Hans-martin Dahse, Helmar Görls, Christian Hertweck
    Abstract:

    NAturAl products of the benzonAphthopyrAnone clAss, such As chArtreusin, ElsAmicin A, gilvocArcin, And polycArcin, represent potent leAds for urgently needed AnticAncer therApeutics And Antibiotics. Since synthetic protocols for Altering their Architectures Are limited, we hArnessed enzymAtic promiscuity to generAte A focused librAry of chArtreusin derivAtives. PAthwAy engineering of the chArtreusin polyketide synthAse, mutAtionAl synthesis, And moleculAr modeling were employed to successfully tAilor the structure of chArtreusin. For the synthesis of the Aglycones, improved synthetic Avenues to substituted coumArin building blocks were estAblished. Using An engineered mutAnt, in totAl 11 new chArtreusin AnAlogs (desmethyl, methyl, ethyl, vinyl, ethynyl, bromo, hydroxy, methoxy, And corresponding (1→2) Abeo-chArtreusins) were generAted And fully chArActerized. Their biologicAl evAluAtion reveAled An unexpected impAct of the ring substituents on AntiproliferAtive And AntibActeriAl Activities. IrrAdiAtion of...

  • Synthetic Remodeling of the ChArtreusin PAthwAy to Tune AntiproliferAtive And AntibActeriAl Activities
    2013
    Co-Authors: Nico Ueberschaar, Kirstin Scherlach, Tom Bretschneider, Hans-martin Dahse, Mikko Metsä-ketelä, Helmar Görls, Christian Hertweck
    Abstract:

    NAturAl products of the benzonAphthopyrAnone clAss, such As chArtreusin, ElsAmicin A, gilvocArcin, And polycArcin, represent potent leAds for urgently needed AnticAncer therApeutics And Antibiotics. Since synthetic protocols for Altering their Architectures Are limited, we hArnessed enzymAtic promiscuity to generAte A focused librAry of chArtreusin derivAtives. PAthwAy engineering of the chArtreusin polyketide synthAse, mutAtionAl synthesis, And moleculAr modeling were employed to successfully tAilor the structure of chArtreusin. For the synthesis of the Aglycones, improved synthetic Avenues to substituted coumArin building blocks were estAblished. Using An engineered mutAnt, in totAl 11 new chArtreusin AnAlogs (desmethyl, methyl, ethyl, vinyl, ethynyl, bromo, hydroxy, methoxy, And corresponding (1→2) Abeo-chArtreusins) were generAted And fully chArActerized. Their biologicAl evAluAtion reveAled An unexpected impAct of the ring substituents on AntiproliferAtive And AntibActeriAl Activities. IrrAdiAtion of vinyl- And ethynyl-substituted derivAtives with blue light resulted in An improved AntiproliferAtive potency AgAinst A colorectAl cAncer cell line. In contrAst, the replAcement of A methyl group by hydrogen cAused A drAsticAlly decreAsed cytotoxicity but mArkedly enhAnced AntimycobActeriAl Activity. Furthermore, mutAsynthesis of bromochArtreusin led to the first crystAl structure of A chArtreusin derivAtive thAt is not modified in the glycoside residue. Beyond showcAsing the possibility of converting diverse, fully synthetic polyphenolic Aglycones into the corresponding glycosides in A whole-cell ApproAch, this work identified new chArtreusins with fine-tuned properties As promising cAndidAtes for further development As therApeutics